Linked Life Data

16942016

Source:http://linkedlifedata.com/resource/pubmed/id/16942016

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
18
pubmed:dateCreated
2006-8-31
pubmed:abstractText
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 microM) is the most potent compound in this series and is quite selective for PNMT versus the alpha2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 microM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
7
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5424-33
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:16942016-Animals, pubmed-meshheading:16942016-Binding Sites, pubmed-meshheading:16942016-Brain, pubmed-meshheading:16942016-Crystallography, X-Ray, pubmed-meshheading:16942016-Humans, pubmed-meshheading:16942016-Hydrogen Bonding, pubmed-meshheading:16942016-Isoquinolines, pubmed-meshheading:16942016-Male, pubmed-meshheading:16942016-Models, Molecular, pubmed-meshheading:16942016-Molecular Structure, pubmed-meshheading:16942016-Phenylethanolamine N-Methyltransferase, pubmed-meshheading:16942016-Radioligand Assay, pubmed-meshheading:16942016-Rats, pubmed-meshheading:16942016-Rats, Sprague-Dawley, pubmed-meshheading:16942016-Receptors, Adrenergic, alpha-2, pubmed-meshheading:16942016-Stereoisomerism, pubmed-meshheading:16942016-Structure-Activity Relationship, pubmed-meshheading:16942016-Sulfonamides, pubmed-meshheading:16942016-Sulfones
pubmed:year
2006
pubmed:articleTitle
Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase.
pubmed:affiliation
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA. ggrunewald@ku.edu
pubmed:publicationType
Journal Article, Comparative Study, In Vitro, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural